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Image-Guided Radiation Therapy for Breast Cancer

Mark P. Bowes, PhD

  *Medical Writer, Portland, Oregon.
  Address correspondence to: Mark P. Bowes, PhD, Medical Writer, 7135 SE 18th Avenue, Portland, OR 97202. E-mail: mpbowes@gmail.com.

Disclosures: Dr Bowes reports having no financial or advisory relationships with corporate organizations related to this activity.

ABSTRACT

Breast cancer is the most frequently diagnosed cancer among women in the United States, excluding cancers of the skin, and the second most common cause of cancer-related mortality. Imaging techniques such as mammography and ultrasound have long been important in the screening, diagnosis, and treatment of breast cancer. Recent advances in imaging techniques, computer software, and robotics have led to the development of new image-guided radiation therapy (IGRT) techniques to improve the accuracy of radiation therapy in patients with breast cancer. Radiation therapy is an important part of the standard of care for women with breast cancer, and is often used in combination with breast-conserving surgery ("lumpectomy") for patients with early disease. Accurate targeting of radiation therapy is essential to kill tumor cells while sparing surrounding healthy tissues, and advances in 3-dimensional computed tomography (CT) scanning and treatment planning now make it possible to provide radiation treatment that is closely matched to the shape of the patient's tumor. However, radiation therapy for most patients involves a series of radiation therapy sessions (eg, 5 days per week for 6 weeks), and the accuracy of treatment may be decreased by patient motion between sessions (eg, changes in how the patient is positioned on the treatment couch from one session to the next) or during the treatment session (eg, movement due to pain or breathing motion). IGRT provides a set of techniques in which imaging technologies (including fluoroscopy, CT scanning, positron emission tomography, and ultrasound) are incorporated into daily radiation treatment in order to improve the targeting accuracy of radiation therapy. IGRT approaches have been extensively studied in other types of cancer (eg, prostate cancer) and are increasingly being used for patients with breast cancer. These techniques have the potential to significantly reduce the amount of healthy tissue that is irradiated during cancer therapy, resulting in better treatment safety and tolerability. Ensuring patient comfort and proper positioning are essential to achieve the potential benefits of IGRT.

Introduction
Breast cancer is the most frequently diagnosed cancer among women in the United States, excluding cancers of the skin, and the second most common cause of cancer-related mortality, following only lung cancer. According to the American Cancer Society, more than 190 000 people are diagnosed with breast cancer each year (including nearly 2000 men), and more than 40 000 patients die from breast cancer.1 Imaging techniques are a critical part of the screening, diagnosis, and treatment of breast cancer. Mammography is very effective for the early detection of small tumors of the breast, and routine screening mammography has been shown to reduce mortality due to breast cancer in many clinical studies.2 The addition of magnetic resonance imaging (MRI) is superior to mammography alone for women with certain high-risk features, including gene mutations that are associated with increased cancer risk.1 For most patients, the diagnosis of breast cancer requires a biopsy to obtain a cell sample from the tumor, which is usually performed using special biopsy needles that are guided by ultrasound. Real-time ultrasound during surgery is often used to locate tumors and to ensure that the surgery is performed correctly.

Recent advances in imaging have led to significant improvements in the accuracy of radiation therapy, which is a routine part of treatment for many patients with breast cancer. Radiation kills tumor cells by damaging and breaking DNA strands, which interrupts the process of cell division and stops tumor growth. An important characteristic of tumor cells is that they are less efficient at repairing DNA damage than are cells from surrounding healthy tissues.3 Patients with breast cancer usually undergo a series of radiation sessions. The radiation dose at each individual session is relatively low, and there is enough time between sessions for DNA repair to take place in normal cells but not in cancerous cells. As a result, DNA damage gradually accumulates in the tumor cells, resulting in the destruction of the tumor with only limited injury to surrounding healthy tissues.3

A critical requirement of radiation therapy is that the radiation must be targeted specifically to the tumor while avoiding healthy tissues that are adjacent to the tumor. Image-guided radiation therapy (IGRT) is a set of techniques that have been introduced to significantly improve the accuracy, effectiveness, and safety of radiation therapy. These techniques build on earlier advances in radiotherapy, such as the use of 3-dimensional (3D) computed tomography (CT) scanning in treatment planning and the ability to control the shape of the radiation beam with a very high level of precision. A wide variety of imaging technologies have been incorporated into IGRT systems.

The Role of Radiation Therapy in Breast Cancer Treatment
Options for the treatment of breast cancer may be divided into 3 general classes: surgery, radiation, and chemotherapy. The treatment of breast cancer is complex and highly individualized, and most patients undergo some combination of these types of treatment. Radiation therapy is usually combined with surgery, chemotherapy, or both. Some of the factors that influence the selection of a specific treatment strategy include the patient's age and general health, the types of treatments that the patient has received previously, whether the cancer is localized to the breast or has spread to the lymph nodes or to other parts of the body, and the presence of certain molecular markers within the tumor that indicate increased tumor aggressiveness.4

Until the 1980s, mastectomy was the most commonly used treatment for women with breast cancer of any size or type.5 Although there were a variety of different approaches and methods, surgical treatment nearly always involved removal of an entire breast and varying degrees of surrounding tissue (eg, the mammary lymph nodes). In contemporary clinical practice, most women with early breast cancer are now treated using breast-conserving surgery combined with radiation therapy, and possibly with chemotherapy as well. In breast-conserving therapy, only the tumor and some surrounding healthy tissue are surgically removed in a procedure known as wide local excision (also called a lumpectomy). Wide local excision is followed by radiation therapy that generally targets the entire breast, with a higher dosage administered to the site from which the tumor was removed. Depending on the specific clinical situation, radiation may also be delivered to additional surrounding sites.4 For example, cancer cells very often migrate from their initial location in the breast to the lymph nodes, and this lymph node involvement is associated with a much higher risk of long-term cancer recurrence than a tumor that is confined entirely to the breast. For this reason, breast cancer therapy will often involve the application of radiation to the surrounding lymph nodes as well as to the breast.

Several clinical studies have demonstrated that breast-conserving treatment is at least as effective as radical mastectomy for long-term tumor control.5,6 However, there are many clinical situations in which mastectomy is still performed, including patients with a history of prior chest wall radiation therapy, the presence of multiple tumors or tumors that cannot be surgically removed without seriously compromising the structure of the breast, pregnancy, or other factors.4

Some patients either elect not to undergo surgery or are not considered candidates for surgery even though their tumors are well localized to a relatively small space. In these cases, radiation with or without chemotherapy may be selected as the primary treatment for breast cancer.4

Finally, patients with advanced breast cancer may have metastatic disease, or spread of the cancer from the breast to distant sites throughout the body (eg, the spinal cord or the liver). Metastatic breast cancer is usually incurable. For these patients, radiation therapy may be administered as a palliative therapy—that is, a therapy that is intended to reduce the patient's discomfort—rather than as a curative treatment.4

For most patients, radiation therapy is administered 5 days a week for a period of several weeks. An alternative approach, accelerated breast irradiation, involves using slightly larger radiation doses at each radiation session, and reducing the total number of sessions. For example, it might be possible to shorten the total duration of radiation therapy from 6 weeks to 3 weeks using accelerated irradiation.7 If radiation is administered after surgery, there is usually a delay of several weeks between surgery and the beginning of radiation therapy to allow the tissues to heal.7 If the patient will receive both chemotherapy and radiation, chemotherapy is usually administered first.

Types of Radiotherapy
Radiation therapy is administered in one of 2 ways. External beam radiation therapy (EBRT) involves the use of a linear accelerator (a device that generates high-energy X-rays by colliding electrons with a metal target) located outside the body to bombard the cancer with high-energy photons (gamma rays or X-rays) or particulate radiation (electrons or protons).3 Radiation beams are applied from several different directions so that the tumor receives a large radiation dose while other surrounding tissues receive only small amounts of radiation. EBRT is the most common type of radiation therapy for patients with breast cancer. In contrast, brachytherapy (also sometimes called internal radiation) involves the use of radioactive seeds, pellets, or catheters, which are placed inside the breast in direct contact with the tumor.7 Brachytherapy may be used alone, or it may be combined with EBRT.

3D Conformal Radiotherapy
Although radiation therapy is useful for killing cancer cells in many different clinical situations, adverse effects are possible if healthy tissues are exposed to radiation. Accurate planning is therefore essential to avoid unnecessary radiation exposure to sites beyond the tumor.

In the past, radiation therapy was planned using a combination of 2-dimensional (2D) radiographs. These radiographs generally provided little contrast of the tumor from surrounding soft tissues.8 As a result, placement of the radiation beams during treatment was usually based on the clinician's judgment of external body contours, combined with estimates of the internal anatomy that were based on bony landmarks. Because patients were treated with as many as 30 individual radiation sessions, some degree of movement of the tumor from session to session was inevitable. One method that was used to control for this motion was the marking or tattooing of the skin to provide surface landmarks to guide therapy.8 However, these methods still were associated with relatively large uncertainties that limited the accuracy of radiation beam targeting.

Due to the limited accuracy of radiation beam placement with 2D images, physicians had to apply radiation to a relatively large area to be sure that all of the tumor was exposed to radiation. This approach had the potential to improve the effectiveness of radiation therapy, but it also exposed other organs to excessive radiation. For example, in patients with breast cancer affecting the left breast, there is a significant risk of radiation exposure to the heart, which in some cases may cause cardiac inflammation or ischemia (reduction of blood flow), injury to the blood vessels surrounding the heart, or other cardiac complications.9

An important advance in cancer care was the development and refinement of conformal 3D radiotherapy, which grew out of advances in 3D imaging. In conformal therapy, 3D reconstructions of tumor volume are integrated with sophisticated computerized planning and delivery of radiation beams that conform to the 3D shape of the tumor.3 This allows the delivery of high radiation doses to the tumor, with less exposure to surrounding tissues. 3D conformal radiotherapy was introduced in the 1980s, and has since become the standard treatment approach for most tumors.10

In 3D radiotherapy, the delivery of radiation can be set to conform to the shape of the tumor using 3 to 4 beams. In the past, this was done with collimators, or metal jaws that widen or narrow to increase or decrease the size of the beam. Once the collimator is set, the beam size remains the same throughout the radiation session. Although collimators provide some flexibility to allow the beam size to be adjusted to match the tumor, a limitation of conventional collimators is that the beams are always rectangular in shape. The shape of the radiation beam was further refined to match the shape of the tumor by using custom-made metal beam blocks, which absorb some parts of the radiation beam and allow other parts to pass. Beam blocks must be individually fabricated for each patient, and are heavy and often difficult to move and position correctly.11 Over time, beam blocks were largely replaced by a device known as a multileaf collimator. The multileaf collimator consists of a large number of small metal leaves, which are individually switched into and out of the radiation beam. Collimators may have more than 100 individual leaves, making it possible to very precisely shape the radiation beam.11 This technique allows the treatment team to create a sharp drop in radiation dose at the edge of the tumor, and provides a very high level of control over how the radiation is applied selectively to the tumor while sparing surrounding healthy tissue.8

Intensity Modulated Radiation Therapy
Intensity modulated radiation therapy (IMRT) is a refinement of 3D conformal radiotherapy that is designed to provide even greater flexibility in radiation exposure to the tumor while decreasing exposure to surrounding tissues. IMRT is similar to conventional 3D radiotherapy, in that multileaf collimators are used to shape and focus radiation beams specifically to the tumor. However, the significant difference between IMRT and 3D radiotherapy is that with IMRT, the technology allows for adjusting the multileaf collimators and beam shapes during the treatment session. The radiation beam is divided in real time into several individual "beamlets" (7-9, compared to 3-4 with 3D conformal therapy), each of which may be individually turned on or off during treatment using a multileaf collimator. This continually adjusts the beam to provide even greater specificity to match the shape of the tumor. In breast cancer, this improved accuracy helps patients to avoid the risk of cardiac toxicity. In addition, the increased accuracy of the radiation beam makes it possible to use higher radiation doses, which may be more effective at killing cancer cells and may also make it possible to complete the course of radiotherapy in fewer sessions.12

Image-Guided Radiation Therapy
Despite the significant advances that have occurred with 3D conformal therapy and IMRT, there are still significant obstacles to accurately targeting breast tumors.

As noted previously, radiotherapy for patients with breast cancer and other types of cancer generally involves a series of radiation doses (referred to as fractions). Dosing sessions are often carried out at daily intervals, although they may sometimes take place more or less frequently, depending on the patient's individual circumstances. 3D conformal radiation therapy and IMRT have improved the delivery of radiation therapy by using highly detailed CT or MRI scans as the basis for treatment planning, combined with adjustable radiation delivery sources to selectively target the tumor. However, in patients who are undergoing repeated sessions of radiotherapy for breast cancer or other types of cancer, there are 2 significant sources of motion that contribute to decreased treatment accuracy.

Interfraction motion is motion that occurs between radiation sessions. Sources of interfraction motion include movement of the tumor within soft tissues, differences in how the patient is positioned on the treatment table from one session to the next, or to other types of set-up errors. One common way to reduce these types of errors is the use of fiducial markers—markers that are placed on or below the skin that can serve as guides to indicate that the patient is positioned properly. For example, gold beads may be implanted at the edge of the surgical site, and when visualized on a radiograph or CT scan, are helpful in confirming that the radiation beam is properly positioned.13

Intrafraction motion is movement that occurs during the radiation therapy session. There are many potential sources of intrafraction motion that can reduce the accuracy of radiation therapy. Patient movement during the session is a significant potential source of treatment error, and some recent advancements in imaging technology may actually contribute to this problem. In the past, when patients were treated with 3D conformal radiation therapy, each radiation dose was usually administered within a short period of time (typically no more than 15 minutes). The radiation oncology team also spent much of their time in close proximity to the patient as landmarks were verified and radiation beam blocks were adjusted, and were there many opportunities during the treatment session to confirm that the patient remained in the proper position. With newer approaches to 3D conformal radiation therapy such as IMRT, individual dosing sessions usually last much longer, often as long as 30 minutes.3 Patients are therefore on the treatment table for much longer periods of time than in the past, increasing the likelihood of patient movement. In addition, radiation therapists are now more often outside the treatment room for the entire procedure.14 Patients are monitored using closed-circuit television, but this may not identify small, subtle motions that are nevertheless large enough to significantly affect the accuracy of treatment.

Other factors may also cause the tumor to move out of position. Internal soft tissues have a tendency to move or shift, which may contribute to beam targeting error. In patients who have had a lumpectomy, the breast structure may change over time as tissue redistributes within and around the cavity.15 Organs may move because of breathing motion or due to organ filling. For example, the position of the prostate gland may vary significantly over time due to changes in the contents of the rectum. If radiotherapy is successful, it may significantly alter the shape of the tumor. The tumor may also move if the patient loses weight, which is relatively common among patients with cancer. The amount of motion caused by these artifacts may appear to be relatively small. However, as noted previously, the trend in radiation therapy in recent years has been to apply higher and higher radiation doses to the tumor, while trying to spare the surrounding tissues. Therefore, even small changes in position can significantly affect the precision with which radiation is delivered. As a result of these various sources of error, some degree of target miss is common in patients who are undergoing EBRT for breast cancer. Several studies have reported that radiotherapy was significantly off-target in approximately 25% to 45% of patients with older treatment planning approaches.15 If the radiation beam is not positioned precisely, there is a risk that the radiation dose to the tumor will be too low.

Image-guided radiation therapy is an emerging set of imaging technologies that further refine IMRT by providing new tools to control for tumor motion. At the most basic level, IGRT uses patient images that are obtained at the time of treatment to make corrections to the treatment plan before the administration of each radiation dose.8 The IGRT process can be divided into 3 steps: simulation, treatment planning, and treatment delivery.16

During simulation, CT scanning is performed while the patient is in the position that will be used during treatment. The CT image may be merged with data from other types of imaging, including MRI, positron emission tomography (PET), or magnetic resonance spectroscopy (MRS). In addition to planning images, the initial simulation process also includes the development and fitting of devices that are intended to help immobilize the patient, including body molds or vacuum bags.8 During simulation, the skin may be marked with small colored ink marks or tattoos to guide radiation beam placement.3,8

In the planning stage, specialized planning computers are used to calculate the radiation dose that will be delivered, the volume of tumor, and healthy tissue to be avoided.16 Several different tumor target volumes may be identified8:

  • Gross tumor volume: The tumor volume as it appears on CT scanning, possibly supplemented with information from other types of imaging (eg, MRI, MRS, or PET).
  • Internal target volume: The sum of the different areas that are occupied as the tumor moves during the patient's breathing cycle.
  • Clinical target volume (CTV): In addition to the apparent tumor volume on imaging, the CTV also includes some surrounding tissue to account for microscopic tumor spread.
  • Planning target volume (PTV): An even larger target area, which is intended to account for variation due to patient movement, organ movement, and changes in positioning.

After simulation and planning are complete, treatment delivery may begin, usually approximately 1 week after simulation and planning.16 Images are obtained before each radiation dose while the patient is on the treatment table to verify correct positioning. This makes it possible to correct the positioning of the patient if needed before the radiotherapy session begins, in order to deliver radiation specifically to the tumor and reduce the risk of radiation-related adverse events. This process begins with the creation of digitally reconstructed radiographs (DRRs) from the CT scans that were obtained in the original simulation session. The DRRs provide a consistent, standardized reference point that defines the precise region of the tumor and the target for radiation therapy. Then, either before or during each IGRT session, "live" images are compared to the reference DRRs, and specialized computer software is used to fuse the acquired images with the expected view of how the tumor should appear. The patient, while immobilized on the treatment couch, is then moved so that the live image and the reference image are brought into alignment.16 IGRT therefore involves 2 distinct components: a technical component, which involves the acquisition and processing of the images; and a medical component, in which physicians review the images and use them to develop and adjust the patient's positioning or the treatment plan.16

Figure 1Types of IGRT
Radiotherapy is administered using an X-ray beam in the megavoltage range, whereas conventional CT scanning employs an imaging beam in the kilovoltage range. For many years, proper positioning of the patient was verified by using the megavoltage treatment beam and radiographic film to produce a radiograph once the patient was positioned on the table. This approach—known as a portal film or port film—provided only a minimal level of detail about the patient's position based on bony landmarks, and could not visualize tumors within soft tissues.16 More recently, techniques have become available to combine high-quality imaging of the tumor during the treatment session to guide the therapy precisely to the tumor. IGRT is a set of procedures that have been developed to correct for motion or position changes due to breathing motion, shifting tumor location within soft tissues, changes in organ filling, or variability in patient positioning in patients undergoing various types of EBRT. IGRT is not a new form of radiation therapy, but is a technique that is used in combination with other methods, including 3D conformal radiation therapy and IMRT to improve the accuracy of treatment.16 As described below, IGRT may be used with many different imaging methods. IGRT systems may be classified into 3 general groups: gantry-mounted systems; in-room systems; and non-ionizing systems (Figure 1).8,17,18

Gantry-Mounted IGRT Systems
Gantry-mounted systems consist of imaging hardware mounted directly to the linear accelerator gantry. These are the most common types of IGRT system currently in use.

Fluoroscopy. A kilovoltage X-ray source and large flat-panel detector may be adapted for use with a linear accelerator for Figure 2real-time fluoroscopy (eg, On Board Imager; Varian Medical Systems, Palo Alto, CA). This approach may be used to visualize motion due to respiration or other causes.12

Cone-beam CT. Kilovoltage X-ray devices may be fitted to the rotating gantry and used to develop 3D volumetric CT images (eg, Synergy X-ray cone-beam system; Elekta Oncology Systems, Norcross, GA).19,20 Cone-beam CT provides high-resolution imaging of tumors and other soft tissues, and is used for daily verification of patient positioning (Figure 2).17 Although this approach has primarily been used to image cancers of the head or abdominal areas, researchers are beginning to develop cone-beam CT for breast scanning as well.21 Research has also examined the use of the megavoltage X-ray source for CT imaging.17 An obstacle to this approach has been that X-ray detectors used in CT scanners have poor resolution of X-rays in the megavoltage range.12

Megavoltage electronic portal imaging. In place of radiographic film, a digital Figure 3electronic portal imaging device (EPID; eg, iView; Elekta Oncology Systems, Norcross, GA) is used with the megavoltage X-ray system to obtain an image of the target, and the same X-ray beam is then used to apply treatment (Figure 3).22 An EPID provides immediate information about patient positioning that may be used with automated systems to correctly position the patient, avoiding the delays in film processing with conventional port films and with greater accuracy.12 In patients with tumors that are located in soft-tissue areas in which it might be difficult to visualize, tumors may be implanted with fiducial markers (eg, gold beads) that will show up well on X-ray imaging. In some cases, megavoltage X-rays may not produce enough contrast between bone and surrounding soft tissues to guide treatment. In these cases, conventional diagnostic X-rays (kilovoltage X-rays) with flat panel detectors may be used for imaging purposes.8

Figure 4Tomotherapy. Conventional radiation beam systems apply radiation from several different directions to target a tumor. Tomotherapy uses a helical gantry that moves around the patient in a circle to irradiate the tumor with smaller radiation beams from all directions. This approach may provide better avoidance of sensitive tumor-free tissue, such as the heart and lungs in patients with left-sided breast cancer.23 It also incorporates a megavoltage CT scan for daily image guidance of patient positioning (Figure 4).23,24

Room-Mounted Systems
A variety of in-room IGRT systems are available that use imaging techniques similar to those described above, but in which the imaging components are fixed to the in-room sites such as the ceiling or floor.17 In-room systems include a variety of fixed X-ray tube and detector combinations, as well as in-room mobile cone-based CT scanners ("CT on rails").17 In-room MRI systems are in development for IGRT, but are not yet extensively used in clinical practice.17

Alternatives to Ionizing Radiation
Ultrasound. Daily B-mode ultrasonic imaging may be used for image guidance and patient positioning for IMRT, with ultrasound images of the tumor or of nearby landmarks superimposed on the planning CT images (eg, B-mode acquisition and targeting device; North American Scientific, Chatsworth, CA).3,8 In some cases, matching a pretreatment ultrasound image to a reference CT image may introduce errors in positioning. One approach to overcome this problem has been to also include an ultrasound scan at the time of treatment planning, which can reduce errors associated with matching ultrasound to CT.17 Recent studies have evaluated high-resolution 3D ultrasound for radiotherapy planning and daily position verification in patients with breast cancer. Some studies have reported that ultrasound was similar or even superior to conventional CT imaging for women undergoing breast conservation treatment, especially for women with dense breasts and small lumpectomy cavities.25

Other alternatives. Other alternatives that do not produce ionizing radiation may also be useful in IGRT.17 Camera-based systems that provide detailed mapping of the patient's body surface can verify positioning and identify patient movement during the treatment session. Implanted radiofrequency tags that are placed near the tumor at the time of surgery permit the localization of the radiation target in 3 dimensions by transmitting radio signals to detectors outside the patient's body.

Controlling for Patient Respiration
As described previously, IGRT uses several techniques to overcome interfraction and intrafraction motion due to patient motion or movement of the tumor within the body. Patient respiration is often a significant source of variability in tumor targeting. For some patients with breast cancer, chest motion during inhalation and exhalation may result in significant movement of the target tumor.9 Techniques have been developed to help control for breathing motion, including asking the patient to hold breathing, or the use of active breathing control devices, in which a computer-controlled valve regulates airflow during inhalation and exhalation.26 Another approach is a deep inspiration breath hold, which reduces motion and also increases the distance between the chest wall and the heart.27 A limitation of these approaches is that they require the compliance of patients who often have limited respiratory capacity, or who may be in pain or discomfort.12 Some IGRT systems use respiratory gating methods, in which the radiation beam is programmed to turn on and off in cycle with the patient's breathing. This allows the beam to strike a moving target at the same point during each breath cycle, effectively canceling out breathing motion.12 For example, the system might use an infrared camera that follows a marker on the patient's chest to trigger the radiation delivery device at the same point in each breath cycle. This allows correction for patient breathing movement but lets the patient breathe naturally and with better comfort.12

Limitations of IGRT
Image-guided radiation therapy is an important advance that allows more consistent delivery of radiation to a tumor over several repeated radiation sessions and despite motion caused by patient breathing. However, there are potential limitations of these technologies.8 IGRT is more time-consuming than conventional radiotherapy approaches due to increasingly complex imaging and radiation administration procedures, which may reduce the number of patients who may be treated on a machine per day. Repeated imaging also exposes the patient to more radiation. The added radiation exposure may be small in relation to the doses used for treatment, and more research is required to understand whether this additional exposure increases the risk of additional malignancies. Although IGRT can help to match the patient's anatomy to images that were acquired during planning, another problem is that soft tissues may be compressed or otherwise moved into different positions during the treatment session.

Finally, patient positioning and immobilization are very important to attain the optimal outcomes with IGRT. Patients must be positioned in a way that is reproducible and that minimizes the potential for patient motion. If the patient is not comfortable, movement while on the treatment table after IGRT images are obtained will negate any advantage of the IGRT procedure.28 Thus, it is important to ensure that the patient is comfortable, and to help patients to tolerate the radiation therapy while minimizing movement.14 Patient education is essential so that patients understand the goals of the procedure, the importance of remaining still so that the tumor can be targeted as accurately as possible, and what to expect during the session. Patients may be given a signal to use during therapy to indicate that they need to stop because of pain, discomfort, nausea, or for other reasons.

Studies of IGRT in Breast Cancer
Image-guided radiation therapy has been examined most extensively for the treatment of prostate cancer. The position of the prostate may shift significantly from session to session due to variability in the contents or positioning of the rectum, and many studies have described the use of IGRT to improve the accuracy of radiation beam targeting for patients with prostate cancer.29 IGRT for breast tumors is at an earlier stage of development, but several recent studies have described the application of IGRT techniques to overcome variability in target location due to soft tissue motion, breathing, and variability in patient set-up for patients with breast cancer. A growing number of recent studies have shown that it is possible to use IGRT to improve beam accuracy and reduce the margin of normal tissue that must be exposed to radiation in patients with breast cancer, and studies are beginning to compare different imaging techniques with one another.

In one recent study, investigators examined the use of implantable, nonmigrating 1.2- x 3-mm gold markers placed at the surgery site in 19 patients who were undergoing accelerated partial breast irradiation (APBI) therapy following lumpectomy.30 In APBI, patients who have undergone lumpectomy are treated with radiation to part of the breast twice daily for 5 days for a total of 10 sessions. Gold markers were imaged at the beginning of each radiation session using orthogonal anterior/posterior (A/P) and lateral megavoltage port films, and the treatment table was then shifted in 3 dimensions (up/down, right/left, A/P) to align the images with the reference DRRs. Imaging resulted in a change of patient positioning to improve beam accuracy in 79% of treatment sessions, with an average shift of 6 mm in each 3D direction. The researchers concluded that the increased accuracy of this procedure made it possible to reduce the margin size from 1 cm to 5 mm, which would spare a considerable amount of surrounding tissue from radiation exposure. The use of the gold markers to identify the tumor site also allowed the investigators to use smaller port films to locate the target without reliance on bony landmarks such as the ribs, clavicle, and sternum.

Another study compared the accuracy of different IGRT approaches in 12 patients undergoing APBI. Similar to the study described previously, these investigators found that kilovoltage imaging of implanted surgical clips was superior to surface imaging using 3D video, kilovoltage imaging of the chest wall, or laser alignment of skin surface markers.31 Even the most accurate method (imaging of surgical clips) was associated with some error, with an average residual positioning error of 2.4 mm, which the authors attributed to factors such as clip migration, tissue motion, patient movement, and other factors. Breast motion due to breathing was especially important in surface imaging, but was less of a factor with clip imaging. When images were gated to patient breathing, the error associated with 3D video was only slightly larger than that of imaging surgical clips.

Recent studies have also examined the use of cone-beam CT to reduce positioning error. In a study of patients undergoing APBI, cone-beam CT was used to visualize the soft tissue of the tumor site to examine how much residual error remained when patients were positioned using 2D kilovoltage or megavoltage images and bony landmarks before each APBI session.32 This study found that the mean positioning error for daily kilovoltage imaging (using cone-beam CT as the reference standard) was approximately 3 to 5 mm in each 3D direction (up/down, right/left, A/P). The authors concluded that the use of cone-beam CT provides little additional positioning benefit beyond kilovoltage/megavoltage imaging for most patients, although it may be useful to improve targeting precision in patients with large breast volumes or patients who require especially tight margins to avoid radiation exposure to surrounding structures. A second study that compared cone-beam CT with the use of skin reference landmarks found that cone-beam CT could reduce targeting errors by an average of approximately 1 to 1.5 mm in each 3D direction, which would yield an average reduction in margin width from 8.8 mm to 3.6 mm.33 These authors noted that the increased accuracy with cone-beam CT may help to avoid large random deviations in beam positioning, which could be especially important in patients receiving accelerated radiation dose schedules. Finally, Kim et al reported on the use of cone-beam CT to visualize surgical clips in patients who were undergoing whole breast irradiation.34 Cone-beam CT visualization of surgical clips, when combined with corrections for breathing, changes in the tumor cavity, and other sources of error, markedly improved beam targeting and reduced the CTV to PTV margin from approximately 1 cm to 6 mm.

Future Developments
In the future, it may be possible to tailor the intensity of radiation exposure inside the target area to match the biological characteristics of different parts of the internal structure of the tumor. For example, different portions of the tumor may vary in radiosensitivity, tissue oxygenation, or cell proliferation rate, and it may be possible to adjust beam intensity to take these differences into account.8 These methods will rely on the use of functional imaging techniques (eg, PET scanning or MRS), which provide information about cellular metabolism.35 In some cases it may be possible to better distinguish active tumor cells from areas of a tumor that consist of dead tissue (necrosis), and this information could be used to decrease the total volume of tissue targeted for radiation therapy.36

Conclusions
External beam radiation therapy for breast cancer requires the accurate targeting of radiation beams to selectively kill tumors while sparing normal surrounding tissues. Several potential sources of error contribute to potential misalignment between the radiation beam and the intended target, and the inclusion of a margin of healthy tissue in the final PTV is therefore essential to ensure eradication of tumors. IGRT is a set of techniques that have been developed to help control for the potential sources of variability in tumor location, including the shifting of soft tissues, breath motion, changes in organ filling, and patient positioning. Twenty years ago, treatment plans typically included a margin of up to 2 cm of healthy tissue in order to ensure that all of the cancer was adequately treated. A decade ago, technologies such as IMRT reduced the margin of healthy tissue to approximately 1 cm, and more recent advances in IGRT have reduced healthy tissue margins to as little as 2 to 5 mm.36 These refinements have made it possible to treat tumors with higher radiation doses, reducing the number of sessions needed and avoiding radiation exposure to surrounding healthy tissue. Maintaining patient comfort is essential to ensuring the safe, effective, and efficient application of these new imaging and radiotherapy techniques.

References
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2. Autier P, Héry C, Haukka J, et al. Advanced breast cancer and breast cancer mortality in randomized controlled trials on mammography screening. J Clin Oncol. 2009;27:5919-5923.

3. Gerber DE, Chan TA. Recent advances in radiation therapy. Am Fam Physician. 2008;78:1254-1262.

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Image-Guided Radiation Therapy for Breast Cancer

 
» Comment From: monica » Posted on: 05/27/2010 11:08 AM
The article was very informative and presented well
 
» Comment From: Jenny » Posted on: 12/23/2010 13:39 PM
I found this article very interesting and reader-friendly.
 
» Comment From: aura » Posted on: 03/30/2011 10:50 AM
A interesting article.
 
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